Comparison of the Clinical Efficacy, Safety, and Postoperative Outcomes Between Peroral Esophageal Myotomy and Laparoscopic Heller's Myotomy With Fundoplication: A Systematic Review

Achalasia, a neurodegenerative disease caused by the progressive destruction of ganglion cells in the myenteric plexus, is accompanied by incomplete relaxation of the lower esophageal sphincter. Laparoscopic Heller's myotomy (LHM) coupled with fundoplication has been the gold standard procedure for achalasia. Peroral esophageal myotomy (POEM) has recently gained popularity as it is minimally invasive, has fewer adverse events, and has excellent short-term outcomes. So, we aimed to compare the clinical efficacy, safety, and postoperative outcomes between LHM and POEM. We did a systematic review by following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines for 2020 and exploring research databases such as PUBMED and PMC Central, Google Scholar, and Research Gate. After appropriate screenings, articles relevant to the review were scrutinized based on the eligibility criteria. Quality assessment tools such as the Newcastle-Ottawa Scale (NOS) and the assessment of multiple systematic reviews (AMSTAR) were used to finalize the articles. A total of 11 articles (seven observational studies, two RCTs, and two systematic reviews) were included in the review after a quality check. The study included 2127 patients, classified into 981 for POEM and 1146 for LHM, who had undergone treatment for achalasia. Most of the studies had a follow-up of ≤ two years. Comparing efficacy, POEM had similar results to LHM in terms of Eckardt scores. However, abnormal DeMeester scores were found in POEM. Adverse events were significantly higher in LHM when compared to POEM in terms of safety. Peroral esophageal myotomy also stood out as having a shorter procedure time, a shorter hospital stay, and lesser odds of being a clinical failure. As for postoperative outcomes, despite treatment with proton pump inhibitors, LHM was more effective in preventing the development of esophagitis compared to POEM due to partial fundoplication. Postoperative reflux and the development of esophagitis remain certain with POEM and need to be followed up with more studies with longer follow-ups. However, POEM still stands as a better choice compared to LHM in terms of efficacy and safety.


Introduction And Background
Achalasia is an uncommon and rare esophageal motility disorder resulting from the loss of inhibitory neurons from progressive destruction and degeneration of the myenteric plexus, thereby leading to impaired relaxation of the lower esophageal sphincter (LES) and esophageal aperistalsis [1].The incidence rate of 0.03 to 1.63 per 100,000 persons per year has recently increased to 2.3 to 2.93 cases per 100,000 [2].According to Eckardt's score, patients usually present with progressive dysphagia of liquids and solids, retrosternal pain, regurgitation, and weight loss.The Chicago classification describes the types of achalasia for diagnosis and differentiation based on high-resolution esophageal manometry (HREM) [1].There is no permanent cure for achalasia.Mild symptoms in elderly women were managed with nitrates and calcium channel blockers.Botulinum toxin injections (BTI) are reserved for candidates unsuitable for effective therapies [3].Current treatment modalities are aimed at palliating symptoms, such as pneumatic dilation (PD) and laparoscopic Heller's myotomy (LHM) with fundoplication being the gold standard.
Heller's myotomy, first described in 1913 by German surgeon Ernst Heller, was modified in 1991 with the advent of the laparoscopic technique and became the gold standard with better long-term outcomes and fewer retreatments compared to PD [4].Recently, an emerging surgical technique called peroral esophageal myotomy (POEM), a type of natural orifice endoscopic surgery, has gained popularity after Inoue et al. performed the procedure on 17 patients in 2008 [5].It combines the advantages of being minimally invasive, like endoscopic dilation, with the precision of a surgical myotomy [6].However, a suggested risk of POEM centers on the lack of fundoplication, which raises concern for the development of gastroesophageal reflux disease (GERD).Short-term outcomes have been excellent irrespective of age, type of achalasia, and prior interventions [7,8].
To date, very few studies have demonstrated the safety and clinical efficacy by comparing the two procedures and found the results to be similar.Therefore, this systematic review aimed to compare and analyze clinical efficacy, safety, and postoperative outcomes with adequate follow-up.

Search Strategy
This systematic review was planned and performed using the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines (PRISMA) 2020 to report the results [9].A comprehensive search of published literature across MEDLINE, PubMed, PMC, Google Scholar, and Research Gate was conducted.

Inclusion and Exclusion Criteria
Observational studies, systematic reviews, and randomized clinical trials (RCT) published in English in the past 10 years were included.Exclusion criteria included articles pertaining to the pediatric population, grey literature, editorials, and animal studies.The full inclusion and exclusion criteria are listed in Table 1  The randomized clinical trials [20,21] were assessed using the Cochrane risk of bias (RoB) assessment.

Dirks et al. [23]
Did the research questions and inclusion criteria for the review include the components of PICO?Yes Yes Did the report of the review contain an explicit statement that the review methods were established to conduct the review and did the report justify any significant deviations from the protocol?Yes Yes Did the review authors explain their selection of the study designs for inclusion in their review?

Data Extraction
Two investigators independently reviewed and extracted the data for all eligible studies related to the topic and screened them using the inclusion and exclusion criteria.Studies were assessed based on Eckardt scores, esophageal function for efficacy, adverse events and complications for safety, and the development of esophagitis in postoperative outcomes.All disagreements were resolved between the reviewers by reaching a consensus.

Results
Using the appropriate MeSH strategy, 936 articles were found in PMC and PubMed.These included systematic reviews, RCTs, and observational studies.A total of 774 articles remained after filtering them using the basic exclusion criteria (non-English articles published before the past 10 years and animal studies).Around 527 articles were left after removing the duplicates.Articles were then carefully screened using abstracts, full-text papers, and detailed inclusion and exclusion criteria (Table 2) by two different authors to reduce the risk of selection bias.Two articles from Research Gate and one article from Google Scholar were then added that were relevant to our review.Eventually, 19 articles underwent quality appraisal using the above checklists.Eight articles were excluded after the quality check, leading to 11 articles (seven observational studies, two RCTs, and two systematic reviews) being included in the final review.A detailed flowchart using PRISMA 2020 is given below in Figure 1 [9].

FIGURE 1: PRISMA 2020 flow diagram for systematic review
The 11 articles that were finalized for this review included seven observational studies, two RCTs, and two systematic reviews.A total of 2127 patients had undergone treatment for achalasia which includes 981 for POEM and 1146 for LHM.A detailed description of the characteristics of the included studies except for systematic reviews is listed below in Table 4.In this systematic review, we were able to compare the safety and efficacy of POEM and LHM in most studies.These compared the Eckardt score, quality of life (QoL) metrics, and timed barium esophagogram (TBE) in the efficacy spectrum.Studies that compared the postoperative reflux between the two techniques found that POEM had a greater propensity for the development of GERD using the esophageal pH study findings, as POEM was not usually coupled with fundoplication compared to LHM [7].Statistically, no difference was found between POEM and LHM in terms of perioperative outcomes and esophageal function [14].Peroral esophageal myotomy was associated with higher short-term clinical outcomes in subtype three, in patients with Chagas disease, and in patients from Latin America [15].The two systematic reviews included observational studies different from the ones we included in this review.

Discussion
By comparing the treatment of achalasia with LHM and partial fundoplication as the gold standard and the use of POEM, studies have shown us the benefits of excellent short-term clinical outcomes with the latter [8].However, there is a serious concern about the long-term GERD symptoms in patients who undergo POEM.The curative treatment modality for achalasia lies in relieving the resting pressure at the LES by mechanical disruption.These included PD, LHM, and the more recent POEM [1].Since POEM allows for a longer myotomy, it has been proposed as a treatment for patients with achalasia type III [16].Several studies have demonstrated the effectiveness, long-term clinical outcomes, and postoperative morbidity of LHM with fundoplication to have excellent results.In one such study done by Krishnamohan et al. on the longterm outcomes of patients undergoing LHM with fundoplication, 85% of the patients did not report any symptoms five years after surgery, with a success rate of 76.1% at the 10-year follow-up [24].
In a study done by Sanaka et al., the results showed that the rate of esophageal exposure was higher in POEM compared to LHM (48.4% vs. 13.6%;p < 0.001) and that GERD symptoms had no statistical difference between POEM and LHM with fundoplication [7].An RCT done by de Moura et al. showed that the rate of reflux esophagitis in the POEM group at one, six, and 12 months of follow-up was significantly higher in contrast to the LHM group (p = 0.014, p = 0.001, p = 0.002, respectively) [21].Assessing the efficacy using esophageal function post-treatment as a parameter, a study done by Sanaka et al. in 2016 compared the existing treatments for achalasia.It was concluded that there was no statistically significant difference between POEM, LHM, and PD at the two-month follow-up (p > 0.005) [17].Therefore, the studies conducted to compare the safety, efficacy, and long-term outcomes are very limited in nature, and with that in mind, this systematic review was designed with the aim of comparing the above-mentioned analysis to determine whether POEM has an extra edge over LHM.

Assessment of Efficacy
All of the included studies assessed the efficacy spectrum between POEM and LHM in terms of Eckardt scores, dysphagia scores, esophageal function post-treatment, TBE, and HREM in varying combinations.
Each of the 11 studies stood out in terms of demographics such as population, study sample, study design, and eligibility criteria.
A prospective cohort study conducted by Kahaleh  The results showed no significant difference in the pre-treatment TBE and HREM parameters in all treatment groups (p > 0.05).The TBE's parameters included barium column height, width, and volume remaining measured at both one-and five-minute intervals.Actual barium height at two-month follow-up decreased by 50% in LHM and 47% in POEM (p = not significant).The HREM was measured on the scale of basal LES pressure and integrated relaxation pressure (IRP), which was reduced to less than 10 mmHg in 72% of LHM and 73% of POEM patients (p =not significant).The study had its limitations in age, BMI, and prior treatments in the POEM group, along with the statistical difference [17].
A cohort study done in a retrospective fashion by Pascale et al. between 2012 and 2015 had 74 patients divided into 32 for POEM and 42 for LHM.Preoperative assessment included an Eckardt score > 3, barium swallow, HREM findings, and esophagogastroduodenoscopy (EGD), which confirmed the diagnosis.The two groups were matched for age, sex, and previous treatment for achalasia.The median preoperative Eckardt score was six for both groups (POEM = 5 to 12, LHM = 4 to 12).A follow-up at 23 and 26 months for POEM and LHM, respectively, showed the Eckardt score was reduced to one in both groups (p = 0.001).This study tells us that there is no significant difference between the groups.However, the study had no predefined criteria for selecting a procedure and included patients who had had prior interventions [18].
In a study done by Schneider et al., patients were matched according to the eligibility criteria, which included Eckardt score, dysphagia severity score, QoL in reflux and dyspepsia (QOLRAD), and GERD-healthrelated quality of life (GERD-HRQL) questionnaire.A total of 25 patients in the POEM and 25 in the LHM group were matched according to the study's criteria.The preoperative mean Eckardt score was 6.6 (+/-2.3) in both groups.Eckardt score < 3 was 91% and 84% in the POEM and LHM groups, respectively (p = 0.444).
The four metrics mentioned above also improved in both groups at a median follow-up of 158 weeks for LHM and 36 weeks for POEM [19].
An RCT conducted by Werner et al. from 2012 to 2015 had a total of 221 patients randomized into LHM with fundoplication (n = 109) and POEM (n = 112).Clinical success was observed in 83% of POEM patients and 82% of LHM patients at two years of follow-up.The esophageal function was assessed objectively by measurement of IRP using HREM, which showed no significant difference (95% CI, −2.26 to 0.76).The gastrointestinal QoL metrics between baseline and 24 months showed no difference as well (95% CI, −4.01 to 4.28).However, this study had a serious limitation since less than 50% of eligible patients participated in the study [20].
A meta-analysis done by Marano et al. included papers between 2005 and 2015 involving 486 patients (n = 196 for POEM and n = 290 for LHM), in which five studies reported no significant difference between POEM and LHM in terms of Eckardt score reduction (p < 0.001).Since significant heterogeneity was present among the studies, random effect analysis was done to reduce the heterogeneity.One of the limitations of the study was that the follow-up was not more than a year, was non-randomized, and included patients with previous esophageal interventions [22].A comparative table depicting the studies comparing the efficacy of the treatments is given in Table 5.
Author This study concluded no significant difference was found in efficacy.
A prospective cohort study done by Hungness et al. in 2012 compared the perioperative outcomes between LHM and POEM in a non-randomized fashion.It included 73 patients (18 in the POEM group, and 55 in the LHM group) who were matched, including the absence of prior treatments.The results showed that operative times were shorter for POEM (113 min vs. 125 min; p < 0.05) and the estimated blood loss was less compared to LHM (<10 ml vs. 50 ml; p < 0.001).Adverse events and hospital stays were similar [14].The safety of the procedures was considered in terms of procedure time, adverse events, and peri-and post-operative complications.In the study done by Kumbhari et al. (49 in the POEM group, 26 in the LHM group), POEM had a significantly shorter mean procedure time compared to the LHM group (102 min vs. 264 min; p < 0.01).
No significant difference was found in hospital stay (3.3 days vs. 3.2 days; p = 0.68), despite having a statistically significant myotomy in POEM vs. LHM (16cm vs. 8 cm; p < 0.01).The overall rate of adverse events was significantly higher in the LHM group (27% vs. 6%; p = 0.01).The adverse events were classified as moderate in seven of the LHM patients, compared to one-third of the patients in the POEM group [16].
In the study done by Kahaleh et al., the rate of adverse events in the POEM group was 17% compared to 14% in the LHM group (p = not significant).These included pneumothoraces, bleeding requiring transfusion, and mediastinitis.The LHM group had longer hospital stays compared to POEM (p < 0.00001) [15].Adverse events in a study done by Werner et al. in

Assessment of Postoperative Outcomes
When compared with POEM in existing literature and clinical practice, the LHM had better postoperative and long-term outcomes.Most of the studies in this review reported that POEM had an increased occurrence of esophagitis compared to LHM.In a study by de Pascale et al. that assessed endoscopy at the one-year follow-up, 20% in each group completed the morphological evaluation for endoscopy, whereas 40% (eight patients) in the POEM group compared to 5% (one patient) in the LHM group had esophagitis (p = 0.004, 95% CI) [18].This esophagitis was classified using the Los Angeles classification.
Schneider et al. reported in their study that postoperative endoscopy was performed in 50% of POEM and 73% of LHM (p = 0.087), where esophagitis was noted to be 53% in POEM and 32% in LHM [19].A study performed by Werner et al. involved 108 POEM patients and 103 LHM patients and assessed the development of GERD clinically, endoscopically, and through pH monitoring.The results showed us that esophageal reflux was higher in the POEM group compared to the LHM group at three months, which was 57% vs. 20% (odds ratio, 5.74; 95% CI, 2.99 to 11.00), and at 24 months, it was 44% vs. 29% (odds ratio, 2.00; 95% CI, 1.03 to 3.85) [20].Another RCT done by de Moura et al. evaluated 40 patients by dividing them into groups of 20 each for POEM and LHM.At the one-, six-, and 12-month follow-ups, the rates of esophagitis were significantly higher in the POEM group compared to the LHM group (p = 0.014, p < 0.001, and p = 0.002, respectively).The rates of esophagitis were 0.0%, 5.6%, and 11.1% in the LHM group and 29.4%, 62.5%, and 64.6% in the POEM group at the one-, six-, and 12-month follow-up, respectively [21].Marano et al. did a meta-analysis that concluded that POEM had worse short-term results in comparison to LHM concerning the development of post-procedure GERD [22].Figure 2 represents the esophagitis rates of the above studies in a simpler format and represents only patients who were able to complete the endoscopic evaluation at their respective follow-up visits.

Conclusions
This systematic review was developed to compare the clinical efficacy, safety, and long-term outcomes between POEM and LHM.In terms of efficacy, Eckardt score reduction pre-and post-procedure and QoL metrics were observed to be similar, with no statistical significance between both procedures.When it comes to safety, POEM has the upper hand in procedure time.However, the rate of adverse events and length of hospital stay were not significant.Postoperative outcomes, including esophagitis and the development of GERD, were noticed more in POEM patients than in LHM patients.Some studies suggest that the initial clinical success rate is relatively higher in POEM and that there is a better prognosis in treating patients with Chagas disease-affected achalasia and achalasia subtype III.
This review will guide future surgeons and physicians in training to keep these findings in mind before selecting a procedure based on patient preference.Even though LHM is coupled with fundoplication, POEM can be considered a safe option given its duration and low rate of adverse events.Long-term outcomes must be evaluated with more RCTs and a larger sample size to have a more complete and detailed validation.

Table 3
depicts the quality of systematic reviews.AMSTAR criteria (

TABLE 4 : Characteristics of the included studies
LHM: Laparoscopic Heller's myotomy, POEM: Peroral esophageal myotomy; PD: Pneumatic dilation; RCT: Randomized clinical trial [16]l.over five years in Latin America included 113 patients, divided into 69 for POEM and 64 for LHM.A total of 35 patients had Chagas disease, out of which 17 were in POEM and 18 in LHM.Eckardt score and HREM pre-and post-POEM have been evaluated at three-, nine-, and 12-month follow-ups.The preprocedural assessment for Eckardt's score was 8.72 vs.7.4in the POEM vs. LHM groups, respectively (p < 0.001).Post-procedure, it was reduced to 1.84 vs.3.6inPOEM vs. LHM (p < 0.001), respectively, at a follow-up of 16 months vs. 22 months in POEM vs. LHM (p = 0.0001).The initial therapy success rate was relatively high, at 86% in POEM vs. 60% in LHM.The preprocedural LES pressure was similar in both groups and was reduced to14.3mmHg in POEM and19.8mmHg in the LHM group post-procedure (p = 0.00231).This study concluded that POEM had a higher rate of initial success and was beneficial in a specific population due to the longer myotomy that it offers[15].Kumbhari et al. conducted a retrospective study for patients with achalasia type III who underwent POEM (n = 49) across the US, Asia, and Europe, which was compared to an LHM (n = 26) done at a single tertiary institution in the US, respectively.Patients were classified according to the Chicago classification criteria.The preprocedural Eckardt stage in LHM compared to POEM had a higher mean baseline (2.85 vs. 2.37, p = 0.001).Eckardt's symptom stage reduced to < 1 was statistically significant with POEM vs. LHM (98.0% vs. 80.8%, p < 0.001) for a follow-up of 8.6 vs.21.5 months, respectively.Since the study was performed in different geographic locations under diverse expertise, a larger proportion of the LHM group had a higher baseline Eckardt stage, and the follow-up in the POEM group was comparatively shorter, which could have led to a favorable bias toward POEM[16].
A retrospective study bySanaka et al.in 2016 compared patients between LHM (n = 142), POEM (n = 36), and PD (n = 22) in terms of esophageal function based on TBE and HREM findings pre-and post-treatment at two months.Most of the patients who underwent POEM and PD had undergone prior treatments compared to the LHM group.

TABLE 5 : Comparative table assessing the efficacy of studies
Lower esophageal sphincter, QOLRAD: Quality of life in reflux And dyspepsia, QoL: Quality of life, GERD: Gastroesophageal reflux disease, IRP: Integrated relaxation pressure, HRQOL: Health-related quality of life TBE: Timed barium esophagogram, HREM: High-resolution esophageal manometry, POEM: Peroral esophageal myotomy, LHM: Laparoscopic Heller's myotomy, LES: [22] involved 221 patients (112 in the POEM group and 109 in the LHM group), revealing 2.7% in the POEM group and 7.3% in the LHM group.Procedure time was found to be shorter in the POEM group than in the LHM group by 13 minutes (95% CI,6.26 to21.36), with no difference in the length of hospital stay[20].No statistically significant difference was noted in the rate of adverse events in the RCT study done by de Moura et al.[21].Dirks et al. conducted a systematic review and metaanalysis between POEM, LHM, and PD on the efficacy scale, perioperative metrics, and safety.The review included 21 studies comparing LHM and POEM, which showed no statistically significant difference in serious adverse events, complications, or hospital stays[23].In a systematic review by Marano in 2016, there was no significant difference in operative time (p = 0.001) or hospital stay (p = 0.049).When comparing gastrointestinal reflux rates, LHM demonstrated better outcomes in contrast to POEM (95% CI: 1.11-1.95,p<0.017)[22].Table6depicts the safety measures in the studies.